Is CITED4 p.Pro18Arg (c.53C>G) pathogenic?

CITED4 p.Pro18Arg (c.53C>G) is classified Uncertain significance in CITED4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-12). AlphaMissense: likely benign (0.1355); Rare (popmax 0.271%, mid).

How common is CITED4 p.Pro18Arg (c.53C>G) in the general population?

CITED4 p.Pro18Arg (c.53C>G) is rare (popmax 0.271%, mid) (gnomAD).

What do computational predictors say about CITED4 p.Pro18Arg (c.53C>G)?

AlphaMissense predicts likely benign (score 0.1355) — an in-silico prediction, not a clinical call.

CITED4 p.Pro18Arg

c.53C>G · rs866248556 · VCV2591822

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1355 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.271%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1355	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -7.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 0.33, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 551 bp · p 0.00038 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.271% Middle Eastern · 10/3,684 alleles

Filtering AF 0.147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.112%

Overall 0.00197% 26/1,322,310 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.271%	368
Remaining individualsnot grpmax-eligible	0.00822%	12,170
South Asian	0.0019%	52,714
European (non-Finnish)	0.00106%	94,220

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CITED4
Protein: p.Pro18Arg
Coding: c.53C>G
MANE Select: NM_133467
dbSNP: rs866248556
Type: single nucleotide variant
Location: chr1:40862075 (GRCh38)
Gene constraint: LOEUF 1.958 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.74
Residue 18: the 'disordered' region

Full CITED4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CITED4 p.Ala116Thr Uncertain significance ★ ⚠ same type
CITED4 p.Ala22Gly Uncertain significance ★ ⚠ same type
CITED4 p.Ala28Val Uncertain significance ★ ⚠ same type
CITED4 p.Ala93Glu Uncertain significance ★ ⚠ same type
CITED4 p.Arg155Cys Uncertain significance ★ ⚠ same type
CITED4 p.Arg155Gly Uncertain significance ★ ⚠ same type
CITED4 p.Arg30Gln Uncertain significance ★ ⚠ same type
CITED4 p.Arg30Trp Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cited4-p-pro18arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown